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The purpose of this study is to quantify combination trastuzumab and radiotherapy to determine their synergy. Methods: In vitro, HER2+ cancer cells were treated with trastuzumab, radiation, or their combination, and imaged to evaluate treatment kinetics. In vivo, HER2+ tumor-bearing mice were treated with trastuzumab and radiation, and assessed longitudinally. An additional cohort was treated and sacrificed to quantify CD45, CD31, \u03b1-SMA, and hypoxia. Results: The interaction index revealed the additive effects of trastuzumab and radiation in vitro in HER2+ cell lines. Furthermore, the results revealed significant differences in tumor response when treated with radiation (p &lt; 0.001); however, no difference was seen in the combination groups when trastuzumab was added to radiotherapy (p = 0.56). Histology revealed increases in CD45 staining in tumors receiving trastuzumab (p &lt; 0.05), indicating potential increases in immune infiltration. Conclusions: The in vitro results showed the additive effect of combination trastuzumab and radiotherapy. The in vivo results showed the potential to achieve similar efficacy of radiotherapy with a reduced dose when combined with trastuzumab. If trastuzumab and low-dose radiotherapy induce greater tumor kill than a higher dose of radiotherapy, combination therapy can achieve a similar reduction in tumor burden.<\/jats:p>","DOI":"10.3390\/cancers14174234","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T23:53:21Z","timestamp":1661990001000},"page":"4234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Quantifying the Effects of Combination Trastuzumab and Radiation Therapy in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Meghan J.","family":"Bloom","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick N.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Radiology, The University of Alabama, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3413-8801","authenticated-orcid":false,"given":"John","family":"Virostko","sequence":"additional","affiliation":[{"name":"LiveSTRONG Cancer Institutes, The University of Texas, Austin, TX 78713, USA"},{"name":"Department of Oncology, The University of Texas Dell Medical School, Austin, TX 78701, USA"},{"name":"Department of Diagnostic Medicine, The University of Texas, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6201-3913","authenticated-orcid":false,"given":"Thomas E.","family":"Yankeelov","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA"},{"name":"LiveSTRONG Cancer Institutes, The University of Texas, Austin, TX 78713, USA"},{"name":"Department of Oncology, The University of Texas Dell Medical School, Austin, TX 78701, USA"},{"name":"Department of Diagnostic Medicine, The University of Texas, Austin, TX 78712, USA"},{"name":"Oden Institute for Computational and Engineering Sciences, The University of Texas, Austin, TX 78712, USA"},{"name":"Department of Imaging Physics, MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3640-3966","authenticated-orcid":false,"given":"Anna G.","family":"Sorace","sequence":"additional","affiliation":[{"name":"Department of Radiology, The University of Alabama, Birmingham, AL 35294, USA"},{"name":"Department of Biomedical Engineering, The University of Alabama, Birmingham, AL 35294, USA"},{"name":"O\u2019Neal Comprehensive Cancer Center, The University of Alabama, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1097\/PAP.0000000000000015","article-title":"HER2 in breast cancer: A review and update","volume":"21","author":"Krishnamurti","year":"2014","journal-title":"Adv. Anat. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6570","DOI":"10.1038\/sj.onc.1206779","article-title":"Biologic and therapeutic role of HER2 in cancer","volume":"22","author":"Menard","year":"2003","journal-title":"Oncogene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.radonc.2017.07.006","article-title":"Concurrent administration of anti-HER2 therapy and radiotherapy: Systematic review","volume":"124","author":"Mignot","year":"2017","journal-title":"Radiother. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/bcr1612","article-title":"HER2 therapy: Molecular mechanisms of trastuzumab resistance","volume":"8","author":"Nahta","year":"2006","journal-title":"Breast Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/sj.onc.1207149","article-title":"Expression of ErbB2 enhances radiation-induced NF-kappaB activation","volume":"23","author":"Guo","year":"2004","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45186","DOI":"10.18632\/oncotarget.9870","article-title":"HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase In Vitro and In Vivo","volume":"7","author":"Hou","year":"2016","journal-title":"Oncotarget"},{"key":"ref_7","first-page":"1113","article-title":"Sensitization of breast cancer cells to radiation by trastuzumab","volume":"2","author":"Liang","year":"2003","journal-title":"Mol. Cancer Ther."},{"key":"ref_8","first-page":"1347","article-title":"Monoclonal antibody to HER-2\/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene","volume":"59","author":"Pietras","year":"1999","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/S0360-3016(00)01358-4","article-title":"Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor","volume":"48","author":"Rao","year":"2000","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41523-021-00242-8","article-title":"De-escalation of radiation therapy in patients with stage I, node-negative, HER2-positive breast cancer","volume":"7","author":"Bazan","year":"2021","journal-title":"NPJ Breast Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5700","DOI":"10.1200\/JCO.2009.23.2025","article-title":"High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller","volume":"27","author":"Litton","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1177\/1758834014530023","article-title":"The PI3K\/AKT\/mTOR pathway in breast cancer: Targets, trials and biomarkers","volume":"6","author":"Paplomata","year":"2014","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5838","DOI":"10.1200\/JCO.2009.22.1507","article-title":"Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer","volume":"27","author":"Spector","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1631\/jzus.B1400221","article-title":"Hypoxia-inducible factor 1 and breast cancer metastasis","volume":"16","author":"Liu","year":"2015","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1007\/s00018-007-7390-6","article-title":"Hypoxia and breast cancer: Prognostic and therapeutic implications","volume":"64","author":"Lundgren","year":"2007","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0093-7754(01)90210-6","article-title":"Oxygen status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy","volume":"28","author":"Vaupel","year":"2001","journal-title":"Semin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s11307-016-0994-1","article-title":"Quantitative [(18)F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer","volume":"19","author":"Sorace","year":"2017","journal-title":"Mol. Imaging Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1634\/theoncologist.2010-0187","article-title":"Optimal sequence of implied modalities in the adjuvant setting of breast cancer treatment: An update on issues to consider","volume":"15","author":"Tsoutsou","year":"2010","journal-title":"Oncologist"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s00232-015-9813-x","article-title":"Different Cell Viability Assays Reveal Inconsistent Results After Bleomycin Electrotransfer In Vitro","volume":"248","author":"Jakstys","year":"2015","journal-title":"J. Membr. Biol."},{"key":"ref_20","first-page":"300","article-title":"Guidelines for the selection of functional assays to evaluate the hallmarks of cancer","volume":"1866","author":"Menyhart","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1177\/1087057115605765","article-title":"A Comparison of Real-Time and Endpoint Cell Viability Assays for Improved Synthetic Lethal Drug Validation","volume":"20","author":"Single","year":"2015","journal-title":"J. Biomol. Screen"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/ng.343","article-title":"Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates","volume":"41","author":"Chuah","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/biot.201400821","article-title":"Optimized Sleeping Beauty transposons rapidly generate stable transgenic cell lines","volume":"10","author":"Kowarz","year":"2015","journal-title":"Biotechnol. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1128\/br.20.4.243-258.1956","article-title":"The calculation of microbial assays","volume":"20","author":"Bliss","year":"1956","journal-title":"Bacteriol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Demidenko, E., and Miller, T.W. (2019). Statistical determination of synergy based on Bliss definition of drugs independence. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224137"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Holleczek, B., Stegmaier, C., Radosa, J.C., Solomayer, E.F., and Brenner, H. (2019). Risk of loco-regional recurrence and distant metastases of patients with invasive breast cancer up to ten years after diagnosis\u2014Results from a registry-based study from Germany. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5710-5"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Song, P.N., Mansur, A., Lu, Y., Della Manna, D., Burns, A., Samuel, S., Heinzman, K., Lapi, S.E., Yang, E.S., and Sorace, A.G. (2022). Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer. Cancers, 14.","DOI":"10.3390\/cancers14041015"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2478\/s11658-014-0191-7","article-title":"Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy","volume":"19","author":"Wang","year":"2014","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1186\/s12935-020-01625-w","article-title":"CD4 T-cell immune stimulation of HER2 + breast cancer cells alters response to trastuzumab In Vitro","volume":"20","author":"Song","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s10549-016-3680-8","article-title":"Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: Preliminary results","volume":"155","author":"Sorace","year":"2016","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15384","DOI":"10.1038\/s41598-021-94887-x","article-title":"Positron emission tomography imaging with (89)Zr-labeled anti-CD8 cys-diabody reveals CD8(+) cell infiltration during oncolytic virus therapy in a glioma murine model","volume":"11","author":"Kasten","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_32","unstructured":"Bloom, M.J. (2020). Characterizing Treatment Induced Alterations of the Tumor Microenvironment Towards Optimizing Therapeutic Regimens in Cancer, The University of Texas at Austin."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/17\/4234\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:20:51Z","timestamp":1760142051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/17\/4234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,31]]},"references-count":32,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cancers14174234"],"URL":"https:\/\/doi.org\/10.3390\/cancers14174234","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,31]]}}}